A long-term goal of the principal investigator's research program is to determine the role of the kidneys in the regulation of arterial pressure during pathophysiological conditions such as salt-sensitive hypertension. A common defect that has been found in all forms of hypertension examined to date, including genetic and experimental models and human essential hypertension, is a hypertensive shift in the pressure natriuresis relationship. A major objective of the current proposal is to examine the role of the renal medullary endothelin system in modulating pressure natriuresis and blood pressure. Data from our laboratory indicates that the production of endothelin is enhanced specifically in the renal medulla by chronic sodium loading. Moreover, data from our laboratory indicate that chronic blockade of ETB receptors within the renal medulla results in significant hypertension in rats on a high sodium intake. The exact mechansims involved in mediating the hypertension, however, are unknown. Compelling evidence indicates a potential interaction between the renal medullary endothelin and cytochrome P450 enzyme /20-Hydroxyeicosatetraenoic acid (20-HETE) systems. Thus, the goal of this proposal is to test the central hypothesis that chronic blockade of renal medullary ETB receptors causes salt-sensitive hypertension by impairing pressure natriuresis. Attenuated pressure natriuresis occurs as a result of a direct influence of ETB receptors on sodium excretion and/or indirectly by decreased synthesis of renal medullary 20-HETE. Furthermore, we propose that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats. A wide range of molecular, biochemical, pharmacological, and physiological techniques will be used to test our hypothesis. Specific aims to be addressed are: 1) To test the hypothesis that the renal medullary endothelin system plays a greater role in regulating sodium excretion and blood pressure as dietary sodium intake is increased 2) To test the hypothesis that the reduction in sodium excretion and elevation in arterial pressure during renal medullary ETB receptor blockade is due to a decrease in renal medullary production of 20 HETE 3) To test the hypothesis that abnormalities in renal medullary endothelin production and/or ETB receptor function mediate the hypertension in Dahl salt-sensitive rats